Process for the preparation of 2,4-dibromo allosteroids



United rates atent fiice 3,l3,h2 Patented Dec. 12, 1951 3,013,929 PRGCESS FOR THE PREPARA'IEON GF 2,4-DEBRGM9 ALLGSTEROEDS Aian Gibson Long, Greenford, England, and John Selwyn Hunt, Montrose, Angus, Scotiand, assignors to Glaxo Laboratories Limited, Greenford, England No Drawing. Filed July 26, 1957, Ser. No, 674,295 Claims priority, application Great Britain July 30, 1956 13 Claims. (tCl. 260-69745) This invention is concerned with the preparation of steroid substances, more particularly 2:4-dibromo-3-ketol l 18-hydroxy allosteroids.

Prednisolone 11,8: l7az2l-trihydroxy-3 :ZO-diketopregna-l24-diene) and cortisol (115:17m21-trihydroxy-3:20- diketopregn-4-ene) are substances of increasing interest in the medical field and thus their syntheses are of considera le commercial importance. One possibility for the synthesis of such compounds involves the use of intermediates in the normal series i.e. from bile acid type starting materials whilst another possibility involves intermediates in the a'llo series, derived for example from such substances as hecogenin. The invention is concerned with the production of certain steroid compounds of the allo series which include in particular substances especially suited as intermediates for the synthesis of cortisol and prednisolone.

4:5ot-dihydrocortisone and its esters are established as intermediates for the production of cortisone, and in general it is known that 3-keto-5a-steroids can be converted into 3-keto-A steroids (the 3-keto-A structure being characteristic of cortisone and other steroids of physiolo gical importance) by a procedure involving dibromination of the 3-keto-5a-steroid followed by rearrangement to a 3-keto-2:4-dibr0mo-5ot-steroid, reaction of the latter with sodium iodide to a 2-iodo-3-keto-A intermediate and subsequent removal of the iodine atom by reduction. In addition prednisone (l-dehydrocortisone) can be directly prepared by the double dehydrobromination of the 2:4-dibromo-3-keto compound above referred to. Frednisone and cortisone however have a keto group in the ll-position as opposed to the hydroxy group present in cortisol and prednisolone.

The application of the above-referred to procedures to analogous compounds having a hydroxy group in the 11- position (in place of the keto group), however leads to difiiculties apparently due to side reactions involving interalia the ll-hydroxy group. In particular in attempts to prepare 2:4-dibromo 4:5u-dihydrocortisol esters we find that the llB-hydroxy group is often eliminated giving rise, in many case, to a A901) compound as the only detectable product. It is therefore an object of this invention to provide a process for the preparation of such steroids wherein this difiiculty is reduced or eliminated.

The formation of 224-dibromo-3-keto-5a-steroids from the corresponding S-keto-Sa compound apparently takes place by first brominating to yield a 2:2dibromo-steroid which is then rearranged in the presence of hydrogen bromide (a specific catalyst for this reaction) to the desired 2:4-dibrorno compound. The 2:2-dibromo compound is normally produced by brominating the starting material with two molecules of bromine and since hydrogen bromide is produced in this reaction, immediate rearrangement to the 2:4-isomer usually takes place.

In investigations which we have carried out on the acidcatalysed dibromination of allosteroids having a keto group in the 3-position and a fi'hydroxy group in the ll-position (to yield the corresponding 2:4-dibromo compounds) we find that the troublesome side-reactions encountered are apparently caused by hydrogen ions derived from hydrogen bromide. The latter substance is,

as stated above, essential as a catalyst for the formation of the 2:4-dibromo compound so that its presence is essential to this reaction. As a result of research we have found that it is possible to carry out the desired reaction in such a way that side reactions are substantially inhibited during the bromination and rearrangement.

This result is accomplished according to the invention by conducting the bromination in a solvent which is inert to the steroid substances present but which is reactive with hydrogen bromide substantially to inhibit its induction of side-reaction but which is insufficiently reactive with hydrogen bromide or bromine substantially to inhibit the desired bromination and rearrangement of the 2:2-dibromo-isomer to the corresponding 2:4-isomer. The solvent chosen (called for convenience an inhibitory solvent), is thus one which reacts in some degree with hydrogen bromide (for example by containing an atom acting as a proton acceptor or by actual chemical combination therewith) to inhibit the side-reactions but not to such an extent as substantially to hinder the formation of the desired 2:4-dibromo compound. As stated the solvent must be inert to the steroids present which in various cases precludes a number of solvents which might otherwise be suitable; thus the dihydroxy acetone sidechain characteristic of various cortical hormones, is well known to be unstable to various primary and secondary lower alcohols in the presence of hydrogen halides.

The suitability of any solvent may in cases of doubt be readily determined by preliminary trial. For example in the case of 4:5ot-dihydr0cortisol esters the starting material may first be contacted with hydrogen bromide in the presence of the selected solvent to ascertain whether dehydration takes place; a fall in rotation in such circumstance would tend to suggest that elimination of the ll-OH group was taking place, which may be confirmed by infra-red spectra evidence, and in some cases by paper chromatography. If the selected solvent passes this preliminary test (i.e. substantially no elimination of the 11- hydroxy group takes place under the stated conditions) the solvent may then be tested to determine whether it is suitable for the actual bromination; again change in rotation is useful evidence of whether or not bromination is taking place.

Particularly suitable inhibitory solvents are those, inert to the steroids in the reaction, which contain an oxygen atom. Of such solvents ethers are particularly suitable both straight chain and cyclic, for example, diethyl ether, diisopropyl ether, dioxan, tetrahydrofuran etc.;.tetrahydrofuran is especially advantageous in that very good yields are obtained withit whilst it is nontoxic and readily handled.

According to the invention therefor We provide a process for the preparation of 2:4 -dibromo-3 keto-llfl-hydroxy-allosteroids by brominating the corresponding 3- keto-llfi-hydroxyallosteroid in which there is used as solvent medium a solvent inert to the steroid reaction components but reactive with hydrogen bromide substantially to inhibit side reactions without substantial inhibitionof the desired reaction.

In the process according to the invention it is generally convenient to add the bromine in solution in a solvent but it may be found that certain of the inhibitory solvents, defined above, e.g.ltetrahydrofuran tend to react with bromine before the latter has a chance to enter the main reaction medium. In these circumstances it is advisable to add the bromine in a solvent which does not act as hydrogen bromide inhibitor. A satisfactory solvent for this purpose is acetic acid. As a result the main solvent medium becomes somewhat diluted. It may in any event be found advantageous to add a non-inhibitory solvent to the main solvent medium to improve its solubility characteristics and/or to moderate its influence on the course of the reaction. Suitable solvents for this ptii isse' md'samrd'meinated hydrocarbons such 2 i WEXAMWJQL zTsTfor eiiafifiila fnethiilne chlonde, chloroform or ethylene dichloride. 1

,The reaction in general iscarried out by adding brorininef" as soltlt iorrof, the starting-steroid the selected iiihibitoryisol ent; preferably-in an 'arnount or gin ant 2. 0 to z sja vanta egmsry 2, 1 ,frnolecfilar equi yalentsahydrq g er ibrorriide' r'n'ay also be added lapart froth that; fiorrmidduring :br'o rnination l lint I total aniount present," ;i.e. that fa 310g? 4 w th th t $f PF sdt r t sisthebw hfi Ishquld b6 s s? .Q tha Fl'hiQh an. e eftect'iriely inhibited by the ol rient gusedt in the casei 0t ii or sam l e t t hydro en. br id i neem {ration should preferably I101; exceed 0.5 and; in the case t t a? s r l V n/ s eti a l-th sh uld J1 ex-i (Feed 10 i ls t im i I YIt t l9 9rri ou i l -t p 2a :4 u-dibromo-l 1 B-hydroxyergostan-3-one A solution of l1fi-hydroXyergostan-3-one (5 g.) in pure dioxan (197 ml.) at 1210., was treated with a drop of A N-hydrogenbrorriide} in dioxan, Y and then bromine (3.93 g5;:"1'.27 "'Hll,;2;0Sf liIlQlQj jwaslladded over 2 mind; The solutionl:(:Q, 125i Njwithfirespect to, hydrogen bromide) wasxallowe'd =to standvfors80flmin;l (so that-the optical rotationor ani aliquot of the solution had ce ased to decrease further) ;,'it' was poured" intoj-dilute 1 sodium bicarbonate solution with stirrin'g,"jand. the precipitated H steroid collected, Washed" with water 'and dried. The solid,.(7.(), g. [lu] l 6f (0., 0 9 .in- CHQl as f bl fa iw". to 0.,

Th w iw d pr pa d according to r the presentin: yention are, as-willbeclear; useful asfintermediate's for the preparation of; steroids having}? ketorgroupiandi unsaturation in r1ng A,and, an llfl-ihydroxy, .group. The 1;;

present-invention isgof particular value "in the preparaterse particularly; the; QI-acetate, which .;substances: .are oi course a of value in 1 they synthesis; of 4 cortisol and pied 1 Q1Q vand.whiohg,mayberepresented as follows: .J

I 1 onto yr/here R ji s h far'd eii or 1' an acyl rgroilpl Substances, of this; formula may-be :converted into :prednisolonevby any convenient method-.zziThey'imaykalso bemonvertedrlto :3;

cortisol; -bya-.the ,method vreformed: :to above: for l thel iconiversion of 2:4-dibromo-4:5m-dihydrocortisone and itstesi ters ,tOjCiOftiSOllfii} 1-; is". *r' ;;;,The startingiimaterrals:;used 5m rthe: p

rocess saccording tor-this, invention canlbe @reptredfhrafii;convenientway.

In the case, offr4z5otedihydrocortisolresters wewtpre'ferf'to startfrorrria 4; 5m=dihydrocontisone tester; protect '-the Iketo groups in their 3.-i and: 20po sitioris abyn thei'rnethod described in" applicatiom SenLNon:5-i8-4,423,2now Patent "No:

2,880,218 reduce the resulting;rleriszatiqei-withf;at:metal hydride nreducing -agent:ie;g.1an alkali; :metal'. or :alkaline earth: metal borohydride=-- followed by decomposition (of the; resulting :ketonic derivativeiand desired ireacyla ti0n';:at: position 211?? ii crfl'hegrednction of;the 1:1;-ketosgroup may; be ;:carried:; outzrwithl 'scidiuirrborohydride; int a 4 rsolve'nt e.-g.,a* mixture ofsalcoholnmethylene chloride and water;

other solvents which may :be used include aqueous :dio'xan;

aqueous tetrahydrofuran'iaswelliascvarious'aqueouslalflQhOlS'. Ill-100i" e e V V. r15 L'The: most" convenient rderi vativeaof .the 3 and 20+lefo groups; to make; fon:the:purpose:x f1protectio'mis :the'tbis- A suitable zitemperature" for. the lredu'ction sfernica'rbaz'orie; :In the case ofthezbis-semicarhazone' of h Az5a-dihydrocorti'sol'gdecomposition lSlIl'lOSt conveniently'reffected withzmin'eral acid;e.g; using '4 'NLhYdrochIoIi'c acid :at TI'OOIII :ternperaturei. T his? is' in contrast :10 -the usual: mode-of decomposing steroid semicarbazones which involves heating inuthel presence: of ii acetic and-ipyruyic acid or the 1 use of nitrous: acid; :2 For 5. the-1': betterffunderstanding o :the ginventio followingaexamplesi are Lgiven' only an illustration: 3 l

"3T0 a solution :of 4 ia-dihydroc'ortisol 2 l acetate (-1 gr) inpure rdi-oxan (43 ml.) at 22 (3.,"wasadded-g' l N- hydrogenlbr omidein dioxan (1' drop) followed lay-"bromine 1(01863: g.; 0.278 ml';; 2.2 mol. equiv); added over 45 'secf! The pale yellowsolution (-0.l-25"N- in HB'r) :was allowedto stand:at20 C. for 50 mini, pouredinto dilute sodium bicarbonate solution and the precipitated dibrorno steroid collected, Washed with Water and dried, "giving a solid: (1111452 J' {@15 47 (cg 0.76 in-CECE), (Found: Br, 28;5-%:) 1.

4:5 hydrocortisoli2lacetate (4:0 dissolved indioiiaij 1,152 min at: 20W,C. and1bromine 1512; Ink) wasji-addfid-j-to th.e; stirred, solution during one.;.-mini1te. After 1 sixty rninutes ;the-;soluti'on was poured, into :,water (about 1600 ml.) 1 containing saturated rsodium bicarbon a e Solution: (60*ml.)..x;lfl'herflocculentg-white precipitate was jcollecteds' after ;tw.o;ht urs,:.;washed; with watenand dried ield 4,942.;

3g aria "01s:eg -wasadasafgve game Tori minute t ir'red solution or -4:j5d-dihy drocor tisjol '21 5 EXAMPLE 6 Bromination of 4:5 ot-dz'hydrocortisol 21-acetate in methylene chloride/diethyl ether A suspension of 4:5tx-dihydrocortisol 21-acetate (3.0 g.) in methylene chloride (108 ml.) and diethyl ether (12 ml.) was treated with bromide (0.84 ml; 2.2 mols.) at room temperature. The rotation of the solution fell from 2.70 immediately after bromination to' 1.75 after 44 mins. The solution was washed with aqueous bicarbonate and water and then dried. Evaporation to dryness gave 2:4-dibromo4:5a-dihydrocortisol 21-acetate as a pale yellow amorphous solid (4.43 g.), [04 +47 (c., 0.4 in CHCl (Br, found 27.7%) which product, on dehydrobromination gave prednisolone acetate identical in all respects with authentic material.

EXAMPLE 7 Preparation 07 2:4-a'ibr0m0-4:5ctdihydr0c0rtisol 21 acetate and cortisol 21-acetate To a solution of 21-acetoxy-11fi:17u-dihydroxy-5apregnane-3:20-dione (1 g.) in pure dioxan (43 ml.) at 22 C. was added 4 N-hydrogen bromide in doxan (1 drop) followed by bromine (0.863 g.; 0.278 ml.) over a period of 45 secs. The pale yellow solution was allowed to stand at 20 C. for 50 min. poured into dilute sodium hydrogen carbonate solution and the precipitated dibromo-steroid collected, washed with water, and dried, giving a solid (1.145 g.), [(11 +47 (c., 0.76 in CHCl (Found: Br, 28.5%.) The crude product was added to a mixture of sodium iodide (3.6 g.) and a bromoacetone solution (5 ml;) (made from bromine (1 ml.) and acetone (30 ml.)) (see Evans et al., I.C.S., 1956, 4356), in acetone (28 ml), the mixture having been refluxed previously for 15 min. After being refluxed for 2 hours, the whole mixture was cooled, filtered to remove sodium bromide, an inert atmosphere being maintained by the addition of solid carbon dioxide. 1.6 N-aqueous chromous chloride was added. After 15 min. the green solution was diluted with water and extracted with methylene chloride. The residue (074 g.), [06113 +109 (c., 0.5 in CHCl from the water-washed extract was suspended in dry ethanol (15 ml.) glacial acetic acid (1 ml.) containing Girard P reagent (0.5 g.) was added and the mixture refluxed for 30 mins. After being cooled to 20 C., the solution was treated with 40 aqueous formaldehyde (2 ml), left to stand for 25 minutes, and poured into a solution of saturated sodium hydrogen carbonate (150 ml.) and water (100 ml.). Ethyl acetate then extracted a by-product (0.19 g.), A max. 237 mu The aqueous phase was acidified to pH 1.0 with 2 N-hydrochloric acid, allowed to stand for several hours and extracted with methylene dichloride, in which it was washed with water, and dried. The residue (0.48 g.) obtained on evaporation was crystallised from ethyl acetate (charcoal). Slightly impure material (0.155 g., 15%), M.I. 201-216" C., was so obtained. Further crystallisations from ethyl acetate, then from acetone gave rhombs of pure cortisol 2l-acetate (0.10 g., 10% M.P. 215- 221' C., +158 (c., 0.6 in dioxan), A max. 242 I11,Lt(e15,200).

EXAMPLE 8 2:4-dibr0m0-4 :5 a-dihydrc0rtis0l 21 -acetate A solution of bromine (2.68 ml.) in glacial acetic acid (25 ml.) was added to a stirred suspension of 4:5a-dihydrocortisol 21-acetate (10 g.) in tetrahydrofuran (100 ml.) to which had been added 6 N-hydrogen bromide in acetic acid (1 ml.). The temperature was maintained at to C. during this addition then rapidly warmed to C. and maintained at that temperature for minutes. The reaction mixture was poured into a stirred suspension of sodium bicarbonate g.) in water (100 ml).

The organic layer was separated and washed with a solution of sodium bicarbonate (8 g.) and ammonium sulphate (50 g.) in Water ml.) and finally dried over anhydrous sodium sulphate. The tetrahydrofuran was removed under reduced pressure to leave 21-acetoxy- 11 3: 17 a dihydroxy-Z 4-dibIOmO-5oc-PT6gnflne-3 :ZO-dione as a yellow brown oil containing about 25% by weight of 4-bromo-butyl acetate. The crude product was dehydrobrominated to give pure prednisolone acetate identical with authentic material.

Although in the foregoing description the process is described with reference to certain compounds it will be clear to those skilled in the art that one may also use a wide variety of other 3-keto-11,B-hydroxy allosteroids within the spirit of the invention. It will also be clear that one can use esters other than 4:5a-cortisol 21-acetate such as the corresponding propionate, butyrate, hemisuccinate, benzoate etc. 7

We claim:

1. In a process for the preparation of a 2:4-dibromo- 3-keto-1lB-hydroxy allosteroid of the ergostane and allopregnane series wherein the corresponding unbrominated 3-keto-11/S-hydroxy allosteroid is brominated at a temperature of from 10 to +40 C. With from 2.0 to 2.5 molecular equivalents of free bromine for each molecular equivalent of said starting allosteroid and hydrogen bromide is produced, the improvement which comprises conducting the reaction in isopropyl ether.

2. In a process for the preparation of a 2:4-dibromo-3' keto-llfi-hydroxy allosteroid of the ergostane and allopregnane series wherein the corresponding unbrominated 3-keto-1lfl-hydroxy allosteroid is brominated at a temperature of from 10 to +40 C. with from 2.0 to 2.5 molecular equivalents of free bromine for each molecular equivalent of said starting allosteroid and hydrogen bromide is produced, the improvement which comprises conducting the reaction in diethyl ether.

3. In a process for the preparation of a 2:4-dibromo-3- keto-l lfl-hydroxy allosteroid of the ergostane and allopregnane series wherein the corresponding unbrominated 3-keto-11i3-hydroxy allosteroid is brominated at a temperature of from 10 to +40 C. with from 2.0 to 2.5 molecular equivalents of free bromine for each molecular equivalent of said starting allosteroid and hydrogen bromide is produced, the improvement which comprises conducting the reaction in tetrahydrofuran.

4. A process as defined in claim 3, in which the bromine is added to the reaction mixture in solution in acetic acid.

5. A process as defined in claim 3, in which the bromine is used in an amount of 2.1 molecular equivalents per molecular equivalent of starting material.

6. A process as defined in claim 3 in which the reaction is carried out at a temperature within the range of +5 to +20 C.

7. In a process for the preparation of a 2:4-dibromo- 4:5a-dihydrocortisol and 21-esters thereof derived from an acid selected from the group consisting of lower alkanoic, succinic and benzoic acids wherein the corresponding unbrominated compound is brominated at a temperature of from 10 to +40 C. with from 2.0 to 2.5 molecular equivalents of free bromine for each molecular equivalent of said unbrominated compound and hydrogen bromide is produced, the improvement which comprises conducting the reaction in isopropyl ether.

8. In a process for the preparation of 2:4-dibromo- 4:5a-dihydrocortisol and 21-esters thereof, derived from an acid selected from the group consisting of lower alkanoic, succinic and benzoic acids wherein the corresponding unbrominated compound is brominated at a temperature of from 10 to +40 C. with from 2.0 to 2.5 molecular equivalents of free bromine for each mo lecular equivalent of said unbrominated compound and hydrogen bromide is produced, the improvement which comprises conducting the reaction in tetrahydrofuran.

9. A process for the preparation of 224-dib1'01I10-415u- :dihYdrociortisot ZLacetate- Whichicomprisesebrorninatifig at a; temperature "of fl'ODlpie-EIQE duo +40 f: CI:-,-;the;correspending. unbrorriinated:compounds iii rtetrahydrofuran with 'from 2.0;10 V2.5 :m61ecu1arj equiva1entsz ofrfre'egbron 1ine,forach molecular:equivalentof, said Unbrominated compound with fake productionof:hydrogenibromide and maintain' g the. total "concentration of hydrogen bromide at avaluemfnotmoredhamilO N'L: v: LQJOQFA process as 'defi'nedin claim 9dr w chihe-reaction is carried out at a temperature-within theirangeiof +5t07+20 1' H fjilu '13. 3'1 ;'.-1

:rf 11.111'1 aiiprrocess fofithepreparation; of a,2:4-ldib'r.omo- ArSw-dihydrocortisol sand ;2'1ester thereof; derived from :an'v acid. selected from the group? consisting-of ilowet iatkanoic; succinic arid .berizoic';ecids wherein vibe .correr spending unbrominatedxcornpoundjs. brominated, at a iempierature :offrom +1091; tQ'ii ifligeiwwithfrom 2.0510 2.5 molecular equivalents of freebromine for each:mo.- lecular equivalent of said unbrominated compound' md hydrogen -h'romide ":isI produced, {the-improvement I which comprises condr ctingithe reaction in diethyl; ether. 11

125 "In :1 process :for the preparation' of a; 2 :4-dibrqmo- -3-k'eto-1'1 fi-hydroxyl'allosteroid .of the er'gdstarie and allohe' corresponding 'iuib-rominated pregnzin'e series wherein t 8 perature of from -10.,to +40f-1C. with from 2.0 to 2.5 molecular e qrl-ivaler ts of free bromine for each molecular equivalefit of said s'tartirig frlljosite fqid' 'zi'rid hydrogen bromide is firodilced;theiihprbvement which comprises 'coriduting the reaction i11 a' mixiure Eof :tetrahydrofuran 'a'nd a sat urzited 'chlorinat'edhydrocarbon. 2-5 5: 1.:- -=v: -i3'i A- process a's; defined in .clai'mulz; in which said Saturafed 'chlo'ririated-" hydrocarbon ivis'rselected from. the group consisting 015 rnethylene. chloride, chloroformi'an'd ethylene dichloride}: 1

. R FE NCES} a 0 1 or ch mi al; swam 945, 1); i bl r b Ki c 1-,Pag li kfir edonn A-CS ?kv n g a iv g pa e 194mm 1 -079, 

1. IN A PROCESS FOR THE PREPARATION OF A 2:4-DIBROMO3-KETO-11B-HYDROXY ALLOSTEROID OF THE ERGOSTANE AND ALLOPREGNANE SERIES WHEREIN THE CORRESPONDING UNBROMINATED 3-KETO-11B-HYDROXY ALLOSTEROID IS BROMINATED AT A TEMPERATURE OF FROM -10* TO +40*C. WITH FROM 2.0 TO 2.5 MOLECULAR EQUIVALENTS OF FREE BROMINE FOR EACH MOLECULAR EQUIVALENT OF SAID STARTING ALLOSTEROID AND HYDROGEN BROMIDE IS PRODUCED, THE IMPROVEMENT WHICH COMPRISES CONDUCTING THE REACTION IN ISOPROPYL ETHER. 